expert opinion

The role of antioxidants in menopause

November 1, 2014

file

Ashok Agarwal, PhD, Director of the Department of Andrology, Center for Reproductive Medicine, Cleveland Clinic, Ohio, USA

“Menopause is a gradual process that occurs over a period of years in females who are typically between 45–55 years of age. It marks the beginning of a woman’s age-related fertility decline via a decrease in the number of ovarian follicles produced. This change in reproductive potential is the direct result of a decline in production of hormones by the ovaries, which causes physical manifestations that negatively impact the quality of life of menopausal women. There is a substantial decrease in the amount of estrogen produced during menopause. Estrogen normally helps to promote female secondary sexual characteristics, such as breast development and female patterned hair growth. Specifically, this hormone increases hepatic production of binding proteins, maintains appropriate fluid balance in the body by allowing for salt and water retention, promotes coagulation, and it allows for a favorable lipid profile via increases in high density lipoprotein (HDL) and decreases in low density lipoprotein (LDL).

Oxidative stress plays an integral part of the aging process and results from the overproduction of free radicals such as reactive oxygen species (ROS), which overwhelm the body’s antioxidant defense mechanisms. Normally, antioxidants neutralize ROS and thus help to prevent over exposure from oxidative stress. However, as the body ages, antioxidant levels decline, leaving the human body susceptible to a variety of age-related pathologies, such as non-alcoholic liver cirrhosis and atherosclerotic heart disease (1, 2). This decline combined with a gradual loss of estrogen in the female reproductive system is highly associated with the various sequelae of menopause such as heart disease, vasomotor disturbances, and osteoporosis (2, 3). The marked reduction in estrogen has been shown to increase levels of oxidative stress in the body, depending on the concentration and chemical structure of this hormone. Specifically, at high concentrations, estrogen tends to have a beneficial antioxidant effect by inhibiting the oxidation of guanine DNA bases. However, at low concentrations, this hormone has pro-oxidant like effects, which include breaks in genetic material, formation of DNA adducts, and oxidation of bases (4). Additionally, serum concentrations of inflammatory cytokines and pro-oxidant biomarkers such as glutathione were found to be higher in postmenopausal women than in premenopausal women (5). The elevation of cytokines and pro-oxidant makers suggests that there is a high degree of oxidative stress in the postmenopausal state (6).

Estrogen has been shown to play a physiologic role in the cardiovascular system by protecting against heart disease. This is facilitated via its atheroprotective effect on plaque stabilization and collateral vessel formation (7, 8). This hormone also has favorable effects on insulin, glucose, and lipoprotein levels in the serum. However, because the antioxidant effect of estrogen is lost once women reach menopause, the incidence of atherosclerosis increases (1). Thus, it is evident that the effects of declining estrogen and other substances during menopause can predispose women to cardiovascular disease. In addition, the hormonal induced increase in inflammatory cytokines within the serum such as tumor necrosis factor, interleukin-4, -10, -12 stimulates osteoclast and osteoblast formation, leading to increased bone turnover and eventually bone loss (6). Overall, it is evident from the role of pro-inflammatory cytokines and estrogen in bone remodeling that oxidative stress is a major contributor to bone density loss in osteoporosis.

Oxidative stress is also involved in the pathogenesis of menopausal symptoms, such as vasomotor disturbances. These disturbances include hot flashes or night sweats: the metabolic rate temporary increases, which often results in sweating, panic, and irritability. Throughout menopause, there are repeated episodes of such vasomotor disturbances, which results in a prolonged increase of the metabolic rate. This increase has been show to contribute to the formation of oxidative stress by placing a hindrance on antioxidants and their function in neutralizing ROS (9).

In  addition to hormone therapy and regular physical activity, the consumption of foods rich in antioxidants has been shown to be helpful in enhancing the beneficial effects of pharmacotherapy for postmenopausal patients (10, 11). Specifically, women who cannot tolerate the adverse side effects of hormone therapy or are prone to develop estrogen-dependent breast cancer may find it advantageous to use dietary antioxidants to control the symptoms of menopause. Supplementation with antioxidants may not only improving the quality of life of menopausal women exposed to high amounts of oxidative stress, but also from other lifestyle-related factors such as smoking, stress, excessive alcohol consumption, and unhealthy eating habits. Among the many antioxidants tested vitamins C (ascorbic acid) and E (alpha-tocopherol) were found to be most beneficial to women in the perimenopausal and postmenopausal phases. The two vitamins can be used to thwart the onset of various disorders associated with an age-related decrease in estrogen. Rich in their antioxidant capacity, these vitamins scavenge free radicals and neutralize oxidative stress (12). One study assessing the effect of these vitamins on postmenopausal women found higher levels of the oxidative stress marker, malonaldehyde, and lower levels of the antioxidant enzymes, catalase and superoxide dismutase, in those who did not incorporate vitamin C and E in their diet (13). The vitamins were not only helpful in achieving a favorable redox balance in the body, but they also are associated with a reduced risk of cardiovascular disease. This is mediated via their inhibition of cholesterol synthesis and LDL- cholesterol oxidation (10, 14).

In regards to the symptoms of menopause, both vitamins have been shown to reduce the intensity and number of hot flashes via promotion of adrenal function. This allows for increased hormonal production, specifically estrogen, allowing for a greater antioxidant defense system in postmenopausal women. When considering vitamin C alone, its intake has been associated with a protective effect on bone. This can be seen through its suppressive action on osteoblast and osteoclast activity, which thereby prevents accelerated bone turnover and eventual bone loss (15, 16). As micronutrients, like all nutrients, may have deleterious effects on the body at very high intakes, it is important that they are used in appropriate doses (10).”

Based on: Doshi S. B. and Agarwal A. The role of oxidative stress in menopause. J Midlife Health. 2013; 4(3):140–146.

References

  1.  Witteman J. C. et al. Increased risk of atherosclerosis in women after the menopause. BMJ. 1989; 298:642–644.
  2.  Becker B. N. et al. Reassessing the cardiac risk profile in chronic hemodialysis patients: A hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J Am Soc Nephrol. 1997; 8:475–486.
  3.  Bittner V. Menopause, age, and cardiovascular risk: A complex relationship. J Am Coll Cardiol. 2009; 54:2374–2375.
  4.  Wang Z. et al. Redox cycling of catechol estrogens generating apurinic/apyrimidinic sites and 8-oxo-deoxyguanosine via reactive oxygen species differentiates equine and human estrogens. Chem Res Toxicol. 2010; 23:1365–1373.
  5.  Signorelli S. S. et al. Behaviour of some indicators of oxidative stress in postmenopausal and fertile women. Maturitas. 2006; 53:77–82.
  6.  McLean R. R. Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep. 2009; 7:134–139.
  7.  McCrohon J. A. et al. Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages: A sex-specific effect. Circulation. 1999; 100:2319–2325.
  8.  Tchernof A. et al. Menopause, central body fatness, and insulin resistance: Effects of hormone-replacement therapy. Coron Artery Dis. 1998; 9:503–511.
  9.  Kronenberg F. Hot flashes: Epidemiology and physiology. Ann N Y Acad Sci. 2006; 592:52–86.
  10.  Kushi L. H. et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996; 334:1156–1162.
  11.  Miguel J. et al. Menopause: A review on the role of oxygen stress and favorable effects of dietary antioxidants. Arch Gerontol Geriatr. 2006; 42:289–306.
  12.  Cook N. R. et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: Results from the women's antioxidant cardiovascular study. Arch Intern Med. 2007; 167:1610–1618.
  13.  Mlakar S. J. et al. Antioxidant enzymes GSR, SOD1, SOD2, and CAT gene variants and bone mineral density values in postmenopausal women: A genetic association analysis. Menopause. 2012; 19:368–376.
  14.  Abdollahzad H. et al. Effect of vitamin C supplementation on oxidative stress and lipid profiles in hemodialysis patients. Int J Vitam Nutr Res. 2009; 79:281–287.
  15.  McSorely P. T. et al. Vitamin C improves endothelial function in healthy estrogen-deficient postmenopausal women. Climacteric. 2003; 6:238–247.
  16.  Morton D. J. et al. Vitamin C supplement use and bone mineral density in postmenopausal women. J Bone Miner Res. 2001; 16:135–140.